Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice

• Published in: Drug and alcohol dependence 2015-11, Vol.156, p.14-20
• Main Authors: Dodman, K, Featherstone, R.E, Bang, J, Liang, Y, Siegel, S.J
• Format: Article
• Language: English
• Subjects: Anesthetics, Dissociative - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Astrocytes - drug effects; Brain - cytology; Brain - drug effects; Ceftriaxone - pharmacology; Cell Count; EAAT2; EEG; Electrodes, Implanted; Electroencephalography - drug effects; Evoked Potentials - drug effects; Excitatory Amino Acid Transporter 2 - genetics; Gamma Rhythm - drug effects; Glia; Glial Fibrillary Acidic Protein - genetics; Ketamine; Ketamine - antagonists & inhibitors; Ketamine - pharmacology; Male; Mice; Mice, Inbred C57BL; Mouse; Psychiatry
• ISSN: 0376-8716; 1879-0046
• DOI: 10.1016/j.drugalcdep.2015.07.1198

Abstract Background Ketamine, an N-methyl- d -aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure. Methods We examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2. Results Juvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone. Conclusions Data suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains.